ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9

Marie F. Smeland; Conor McClenaghan; Helen I. Roessler; Sanne Savelberg; Geir Åsmund Myge Hansen; Helene Hjellnes; Kjell Arne Arntzen; Kai Ivar Müller; Andreas Rosenberger Dybesland; Theresa Harter; Monica Sala-Rabanal; Chris H. Emfinger; Yan Huang; Soma S. Singareddy; Jamie Gunn; David F. Wozniak; Attila Kovacs; Maarten Massink; Federico Tessadori; Sarah M. Kamel; Jeroen Bakkers; Maria S. Remedi; Marijke Van Ghelue; Colin G. Nichols; Gijs van Haaften

doi:10.1038/s41467-019-12428-7

ABCC9-related Intellectual disability Myopathy Syndrome is a K_ATP channelopathy with loss-of-function mutations in ABCC9

Marie F. Smeland
, Conor McClenaghan
, Helen I. Roessler
, Sanne Savelberg
, Geir Åsmund Myge Hansen
, Helene Hjellnes
, Kjell Arne Arntzen
, Kai Ivar Müller
, Andreas Rosenberger Dybesland
, Theresa Harter
, Monica Sala-Rabanal
, Chris H. Emfinger
, Yan Huang
, Soma S. Singareddy
, Jamie Gunn
, David F. Wozniak
, Attila Kovacs
, Maarten Massink
, Federico Tessadori
, Sarah M. Kamel

Jeroen Bakkers, Maria S. Remedi, Marijke Van Ghelue, Colin G. Nichols, Gijs van Haaften

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

Mutations in genes encoding K_ATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of K_ATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional K_ATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing K_ATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of K_ATP loss- versus gain-of-function.

Original language	English
Article number	4457
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12428-7
State	Published - Dec 1 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

First, we thank the patients and families for their participation and consent to publish this work. Help from the following was greatly appreciated: Radiologist Marit Herder (MRI descriptions). Neurologist Synnøve Jensen (neurological examinations), geneticists Ragnhild Glad and Valeria Marton (initial evaluation and diagnostics in the two families). Cardiologists Assami Rösner and Eivind Øygard Fosse (discussion of cardiac features), ENT specialist Dagny Hemmingsen (hearing evaluation), the National Neuromuscular Center, Tromsø, Norway. We acknowledge the support from the E-Rare Joint Transnational Cantú Treat program (I-2101-B26), and NIH grant HL140024 (to CGN). Partial support for the behavioral work was provided by the Intellectual and Developmental Disabilities Research Center at Washington University (NIH/NICHD U54 HD087011; DFW). C.Mc. is supported by American Heart Association Fellowship (19POST34380407).

Funders	Funder number
American the American Heart Association	19POST34380407
Norges Idrettshøgskole	HL140024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

Access to Document

10.1038/s41467-019-12428-7

Cite this

Smeland, M. F., McClenaghan, C., Roessler, H. I., Savelberg, S., Hansen, G. Å. M., Hjellnes, H., Arntzen, K. A., Müller, K. I., Dybesland, A. R., Harter, T., Sala-Rabanal, M., Emfinger, C. H., Huang, Y., Singareddy, S. S., Gunn, J., Wozniak, D. F., Kovacs, A., Massink, M., Tessadori, F., ... van Haaften, G. (2019). ABCC9-related Intellectual disability Myopathy Syndrome is a K_ATP channelopathy with loss-of-function mutations in ABCC9. Nature Communications, 10(1), Article 4457. https://doi.org/10.1038/s41467-019-12428-7

@article{31369ec6cc0442a18654178e85183b81,

title = "ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9",

abstract = "Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cant{\'u} syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cant{\'u} syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.",

author = "Smeland, \{Marie F.\} and Conor McClenaghan and Roessler, \{Helen I.\} and Sanne Savelberg and Hansen, \{Geir {\AA}smund Myge\} and Helene Hjellnes and Arntzen, \{Kjell Arne\} and M{\"u}ller, \{Kai Ivar\} and Dybesland, \{Andreas Rosenberger\} and Theresa Harter and Monica Sala-Rabanal and Emfinger, \{Chris H.\} and Yan Huang and Singareddy, \{Soma S.\} and Jamie Gunn and Wozniak, \{David F.\} and Attila Kovacs and Maarten Massink and Federico Tessadori and Kamel, \{Sarah M.\} and Jeroen Bakkers and Remedi, \{Maria S.\} and \{Van Ghelue\}, Marijke and Nichols, \{Colin G.\} and \{van Haaften\}, Gijs",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-12428-7",

language = "English",

volume = "10",

number = "1",

}

Smeland, MF, McClenaghan, C, Roessler, HI, Savelberg, S, Hansen, GÅM, Hjellnes, H, Arntzen, KA, Müller, KI, Dybesland, AR, Harter, T, Sala-Rabanal, M, Emfinger, CH, Huang, Y, Singareddy, SS, Gunn, J, Wozniak, DF, Kovacs, A, Massink, M, Tessadori, F, Kamel, SM, Bakkers, J, Remedi, MS, Van Ghelue, M, Nichols, CG & van Haaften, G 2019, 'ABCC9-related Intellectual disability Myopathy Syndrome is a K_ATP channelopathy with loss-of-function mutations in ABCC9', Nature Communications, vol. 10, no. 1, 4457. https://doi.org/10.1038/s41467-019-12428-7

TY - JOUR

T1 - ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9

AU - Smeland, Marie F.

AU - McClenaghan, Conor

AU - Roessler, Helen I.

AU - Savelberg, Sanne

AU - Hansen, Geir Åsmund Myge

AU - Hjellnes, Helene

AU - Arntzen, Kjell Arne

AU - Müller, Kai Ivar

AU - Dybesland, Andreas Rosenberger

AU - Harter, Theresa

AU - Sala-Rabanal, Monica

AU - Emfinger, Chris H.

AU - Huang, Yan

AU - Singareddy, Soma S.

AU - Gunn, Jamie

AU - Wozniak, David F.

AU - Kovacs, Attila

AU - Massink, Maarten

AU - Tessadori, Federico

AU - Kamel, Sarah M.

AU - Bakkers, Jeroen

AU - Remedi, Maria S.

AU - Van Ghelue, Marijke

AU - Nichols, Colin G.

AU - van Haaften, Gijs

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.

AB - Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.

UR - https://www.scopus.com/pages/publications/85072847290

UR - https://www.scopus.com/pages/publications/85072847290#tab=citedBy

U2 - 10.1038/s41467-019-12428-7

DO - 10.1038/s41467-019-12428-7

M3 - Article

C2 - 31575858

AN - SCOPUS:85072847290

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4457

ER -